A Novel Approach to Partition Central and Peripheral Airway Nitric Oxide

doi:10.1378/chest.13-0843

Chest

Volume 145, Issue 1, January 2014, Pages 113-119

https://doi.org/10.1378/chest.13-0843 Get rights and content

Background

Determining the site of airways inflammation may lead to the targeting of therapy. Nitric oxide (NO) is a biomarker of airway inflammation and can be measured at multiple exhalation flow rates to allow partitioning into bronchial (large/central airway maximal nitric oxide flux [J’awno]) and peripheral (peripheral/small airway/alveolar nitric oxide concentration [Cano]) airway contributions by linear regression. This requires a minimum of three exhalations. We developed a simple and practical method to partition NO.

Methods

In 29 healthy subjects (FEV₁, 97% ± 3% predicted), 13 patients with asthma (FEV₁, 90% ± 4% predicted), 14 patients with COPD (FEV₁, 59% ± 3% predicted), and 12 patients with cystic fibrosis (CF) (FEV₁, 60% ± 3% predicted), we measured the area under the curve of the NO concentration/exhalation time plot (AUC-NO) at exhalation flow rates of 50, 100, 200, and 300 mL/s. We determined the change of the total AUC-NO production (δAUC-NO) among the four different exhalation flow rates and compared these levels to Cano and J’awno indices measured conventionally by linear regression.

Results

The change in AUC-NO between increasing exhalation flow rates of 50 to 200 mL/s (δAUC-NO_50-200) was strongly correlated with J’awno in all patient groups as follows: healthy subjects (r = 0.94, P < .001), patients with asthma (r = 0.98, P < .001), patients with COPD (r = 0.93, P < .001), and patients with CF (r = 0.74, P < .05). In all subjects, AUC-NO at an exhalation flow rate of 200 mL/s (AUC-NO₂₀₀) correlated with Cano (r = 0.69, P < .01).

Conclusions

The bronchial production of NO can be determined by measuring δAUC-NO_50-200, whereas AUC-NO₂₀₀ measures its peripheral concentration. This approach is simple, quick, and does not require sophisticated equipment or mathematical models.

Section snippets

Patients

Twenty-nine healthy volunteers (20 men; mean age, 38 ± 2 years; FEV₁, 97% ± 3% predicted) were enrolled in the study (Table 1). We also studied 13 steroid-naive patients with asthma (eight men; mean age, 48 ± 8 years; FEV₁, 90% ± 4% predicted) whose condition was diagnosed according to American Thoracic Society criteria¹⁸; 14 patients with COPD (10 men; mean age, 63 ± 2 years; FEV₁, 59% ± 3% predicted), all ex-smokers with a ≥ 20-pack-year smoking history and without a history of allergic

Single-Breath Feno and Linear Regression Method

Feno was significantly elevated in patients with asthma (73.23 ± 11.19 parts per billion [ppb], P < .01), whereas it was significantly reduced in patients with CF (11.79 ± 2.14 ppb, P < .01) compared with healthy subjects (34.68 ± 3.59 ppb). Patients with COPD (37.30 ± 10.97 ppb) had similar levels to those of the healthy subjects (Fig 2A).

J’awno was significantly elevated in patients with asthma (189.00 ± 28.76 ng/s, P < .01) but significantly reduced in patients with CF (33.00 ± 5.93 ng/s, P

Discussion

This study shows that the bronchial production of NO and its alveolar concentration can be calculated by a novel method that measures the changes in AUC-NO values resulting from exhalations at slow and fast flow rates. The results agree with J’awno and Cano estimated conventionally by a linear regression equation. The advantage of the present method is that it does not require sophisticated calculations and specific software and may allow wider application of these measurements within the

Conclusions

This simpler and more patient-friendly method for the partitioning of exhaled NO can be applied in different groups of patients with pulmonary disease. The direct point-by-point measurement takes into account parallel compartments and sequential filling of the alveoli, potentially reducing the limitations associated with the conventional method. Further studies may support the growing evidence that the partitioning of exhaled NO may complement the measurement of total Feno. Clinical studies

Acknowledgments

Author contributions: Dr Paredi had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Paredi: contributed to the study design; data analysis; and writing, editing, and final approval of the manuscript.

Dr Kharitonov: contributed to the study concept and design and writing, editing, and final approval of the manuscript.

Ms Meah: contributed to the study design, recruitment of patients, NO measurements, and

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The full text of 70 articles was read, excluding articles that did not meet the requirements. Ultimately, 19 studies were included.15-33 Reasons for exclusion included the following: specific data were lacking or data were not expressed as mean ± standard deviation, median and range or median and quartile range (n = 11); it was not clear whether the COPD group was stable, or the COPD patients did not meet the criteria for stable status (n = 12); FeNO was not measured online or was not measured at a constant flow rate of 50 mL/s (n = 28).
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A search of the Medline, Embase, Web of Science, ClinicalTrials.gov and The Cochrane Library databases was performed in August 2019. The literature search was restricted to articles published in English. Studies were included if they reported data addressing FeNO levels in patients with stable COPD and healthy controls. Review Manager version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) was used for meta-analysis.
A total of 19 studies were included. Analysis revealed that FeNO levels in patients with stable COPD were higher than those in the healthy control group (mean difference [MD] 2.49 [95% confidence interval {CI} 0.99-4.00]; P < 0.05), those in nonsmoking patients with stable COPD were higher than those in the healthy control group (MD 5.04 [95% CI 2.19-7.89]; P < 0.05) and those in smoking patients with stable COPD were not higher than those in the healthy control group (MD 0.30 [95% CI −2.81 to 3.41]; P = 0.85). FeNO measured using a chemiluminescence analyzer in nonsmoking patients with stable COPD was higher than those in the healthy control group (MD 4.84 [95% CI 1.83-7.86]; P < 0.05).
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FeNO is a biomarker of reactive airway inflammation, especially airway eosinophilic inflammation. FeNO reflects both the central and peripheral airways, even alveolar inflammation [12]. Keen et al. conducted a study of children with asthma aged 6 to 18 and showed that FeNO reflects bronchial hyperresponsiveness and is closely related to small airway function [27].
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A total of 79 preschool children(3–6 year old) with asthma and 25 healthy preschool children who visited a paediatrician were enrolled in this study. All of the children were tested for allergens, respiratory system resistance (at 5 and 20 Hz [R5, R20]), respiratory system reactance (at 5 Hz [X5]), the resonant frequency of reactance (Fres), and the area under the reactance curve (between 5 Hz and Fres (reactance area [AX]) using IOS and FeNO. A paediatric respiratory specialist who was unaware of the IOS and FeNO results assigned children with asthma to either the asthma-controlled group (n = 27) or the asthma-uncontrolled group (n = 52) based on the Global Initiative for Asthma (GINA) criteria. A healthy control group (n = 25) was also included. The relationships between the FeNO and IOS values as well as the asthma control of the three groups were analysed, and the areas under the curve (AUCs) were calculated for each measure.
(1) During the controlled group, means±standard deviations of AX, R5-20, R5, X5 and FeNO were 26.15 ± 7.534, 3.52 ± 1.311,9.97 ± 1.576,-3.85 ± 0.572,-3.85 ± 0.572. During the uncontrolled group, means±standard deviations of AX,R5-20,R5,X5 and FeNO were 38.34 ± 13.563,5.36 ± 1.545,11.41 ± 2.029,-5.07 ± 1.554,36.40 ± 21.07. Among preschool children, significant differences were observed between the controlled and uncontrolled group with regard to the small airway functional parameters (AX, R5-20, R5, and X5) and FeNO(P < 0.05).(2) A receiver operating characteristic (ROC) analysis showed that the AUCs were 0.786 for FeNO alone, 0.751 for X5 alone, and 0.866 for X5 combined with FeNO (cut-off value: 27 ppb).
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Funding/Support: Dr Usmani is a recipient of a UK National Institute for Health Research (NIHR) Career Development Fellowship. This project was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton & Harefield NHS Foundation Trust and Imperial College London.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original ResearchAllergy and AirwayA Novel Approach to Partition Central and Peripheral Airway Nitric Oxide

Background

Methods

Results

Conclusions

Section snippets

Patients

Single-Breath Feno and Linear Regression Method

Discussion

Conclusions

Acknowledgments

Chest

Chest

Chest

J Allergy Clin Immunol

Chest

Chest

Chest

Lancet

Chest

Analysis of expired air for oxidation products

Am J Respir Crit Care Med

ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005

Am J Respir Crit Care Med

Assessing and treating small airways disease in asthma and chronic obstructive pulmonary disease

Ann Med

Treating the small airways

Respiration

A two-compartment model of pulmonary nitric oxide exchange dynamics

J Appl Physiol

Increased bronchial nitric oxide production in patients with asthma measured with a novel method of different exhalation flow rates

Ann Med

Alveolar nitric oxide in adults with asthma: evidence of distal lung inflammation in refractory asthma

Eur Respir J

Exhaled nitric oxide from lung periphery is increased in COPD

Eur Respir J

Original Research
Allergy and Airway
A Novel Approach to Partition Central and Peripheral Airway Nitric Oxide